The present invention relates to isoxazole and oxadiazole compounds having anti-inflammatory activity, pharmaceutical compositions that contain the compounds, and methods for their production and use.
Interleukin-8 (IL-8) is a chemotactic cytokine whose primary role seems to be to chemoattract and activate polymorphonuclear leukocytes (PMN; neutrophil). Inhibition of the actions of IL-8 on the neutrophil is expected to inhibit their recruitment to sites of inflammation, their activation, and thus inhibit the release of neutrophil products such as lysosomal enzymes (elastase, myeloperoxidase, cathepsins, etc.) which are responsible for much of the tissue damage associated with inflammation.
IL-8 is a member of the C-X-C family of chemokines which includes platelet factor 4 (PF4), neutrophil activating peptide-2 (NAP-2), melanoma growth stimulatory activity (MGSA) chemokines, interferon-xcex3 induced peptide (IP-10), and the like (reviewed in Kemeny et al., Skin. Int. Arch. Allergy Immunol. 104:317-22, 1994; Schroder, J. and E. Christophers, xe2x80x9cThe Biology of NAP-1/IL-8, a Neutrophil-Activating Cytokine,xe2x80x9d In: Granulocyte Responses to Cytokines, Marcel Dekker, N.Y., pp. 387-416, 1992.; Bickel, M., J. Periodontal. 64:456-460, 1993.; Baggiolini et al., Chest 105(Suppl. 3):955-85, 1994). IL-8 is produced primarily by monocytes and macrophages, but is also produced by a variety of other cell types including synovial cells and keratinocytes (Schroder, J. and E. Christophers, supra; Kemeny et al., supra). Its production can be triggered by inflammatory stimuli such as IL-1, TNFxcex1, LPS, and IL-4, (Streiter et al., J. Lab. Clin. Med. 123:183-97, 1994; Zwahlen et. al., Int. Rev. Exp. Pathol. 348, 27-42, 1993). IL-8 is a potent chemotactic agent for neutrophils, and can stimulate neutrophil degranulation and induce basophil histamine release (reviewed in Kemeny et al., supra). Neutrophils are prime players in the inflammatory response and responsible for extensive tissue damage due to the release of lysosomal enzymes. High levels of IL-8 have been detected in lavage fluids of cystic fibrosis patients, sites of atherosclerosis and ischemic reperfusion injury, in the synovial fluid and cells from rheumatoid arthritis patients and also in psoriatic plaques (Streiter et al., supra; reviewed in Kemeny et al., supra; Lemster et al., Clin. Exp. Immunol. 99:148-154, 1995). If IL-8 activity can be inhibited by preventing its binding to cell surface receptors, neutrophils can be prevented from accumulating at the site of inflammation.
Specificity of IL-8 activation occurs through specific cell surface receptors (Horuk, R. The Interleukin-8 receptor Family: From Chemokines to Malaria. Immunology Today, 1994; Strosberg, A. D., Eur. J. Biochem. 196:1-10, 1991). IL-8 receptors have 7 transmembrane domains, are members of the rhodopsin family of receptors, and are linked to G-proteins for signal transduction (Baggiolini et al., supra; Wu et al., Science 261:101-3, 1993). Knockout mouse studies of the IL-8 receptor have shown a lack of neutrophil migration in vivo in response to an inflammatory signal, demonstrating the importance of this cytokine in inflammation (Moore, M., The Role of the Murine IL-8 Receptor and its Ligand in Chemotaxis and Inflammation, IRA Meeting, January 1995). Neutralizing antibody studies have also shown a decrease in neutrophil migration by inhibiting IL-8 binding to the neutrophil receptor (Broaddus et al., J. Immunol. 152:2960-7, 1994). Clinical indications for the use of an IL-8 receptor antagonist include: adult respiratory distress syndrome (ARDS), rheumatoid arthritis (RA), myocardial perfusion injury, ulcerative colitis, psoriasis, chronic obstructive lung disease (COPD), cystic fibrosis (CF), and some cancers which have been shown to involve high levels of IL-8 production.
Isoxazoles have been reported to be useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex or the vitronectin receptor for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders. 4,5-Dihydronaphth[1,2-c]isoxazole derivatives are reported to be useful as serotonin 5-HT3 antagonists useful for the treatment of anxiety, psychiatric disorders, nausea, vomiting and drug dependency. Isoxazole derivatives are also reported to be useful as herbicides.
JP 60054375 (Chisso Corp., Japan, 1985) discloses, among other compounds, isoxazoles of the formula 
wherein substituents are as described in the reference, which are stated to be xe2x80x9cuseful as liq. crystal components.xe2x80x9d
U.S. Pat. No. 5,476,866 to Kuo et al. discloses isoxazoles of the formula 
wherein substituents are as described in the reference, which are stated to have xe2x80x9canti-proliferative, anti-inflammatory and anti-tumor activity.xe2x80x9d
U.S. Pat. No. 5,633,272 to Talley et al. discloses substituted isoxazolyl compounds of the formula 
wherein substituents are as described in the reference, which are stated to be useful xe2x80x9cin treating inflammation and inflammation-related disorders.xe2x80x9d
U.S. Pat. No. 5,814,627 to Schwab et al. discloses 3,5-disubstituted and 3,4,5-trisubstituted 2-isoxazolines and isoxazoles of the formula 
wherein substituents are as described in the reference, which are stated to be xe2x80x9csuitable for preparing medicaments for the therapy of inflammations, asthma, rheumatoid diseases and auto-immune diseases.xe2x80x9d
The invention provides a compound of Formula I or II, 
wherein
R is one or two independent members selected from hydrogen, halogen, C1xe2x88x926 alkyl, C1-6alkoxy, alkoxycarbonyl, aryl, aryloxy, hydroxy, nitro, sulfonylamino, trifluoromethyl, cyano, methylenedioxy, and ethylenedioxy;
X is nitrogen or CR1 wherein R1 is selected from hydrogen, alkyl, aryl, halogen, CH2OH, carbomethoxy, and carboethoxy;
Y is CR or nitrogen;
L is selected from oxygen, sulfur, xe2x80x94N(R2)xe2x80x94, xe2x80x94C(O)NR2xe2x80x94,xe2x80x94R2NC(O)xe2x80x94,xe2x80x94C(O)Oxe2x80x94, and xe2x80x94OC(O)xe2x80x94, wherein R2 is hydrogen or C1-6alkyl; and
Z is NR3R4 or saturated heterocyclyl having one or two nitrogen as heteroatom, wherein R3 and R4 are independently selected from hydrogen, C1-6alkyl, and phenyl and the heterocyclyl group may be substituted with one or more independent substituents selected from halogen, oxo, OH, alkyl, amino and alkoxy;
Alk is a branched or unbranched alkyl group;
n is an integer from 0-6 representing the number of carbons in the alkylene group, with the proviso that when L is oxygen, sulfur, or nitrogen, n is an integer from 2-6;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof.
Compounds of the above formulae are useful as anti-inflammatory agents for the treatment of adult respiratory distress syndrome (ARDS), rheumatoid arthritis (RA), myocardial perfusion injury, ulcerative colitis, psoriasis, chronic obstructive lung disease (COPD), cystic fibrosis (CF), and cancers in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by action of IL-8, which comprises administering to said subject a therapeutically effective amount of a compound of Formula I or II.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by action of IL-8, which comprises administering to the subject a prophylactically effective amount of a compound of Formula I or II.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.